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Quinazoline-based thymidylate synthase inhibitors: relationship between structural modifications and polyglutamation
A L Jackman1, R Kimbell, M Brown
1CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK.
Anti-Cancer Drug Design
|October 1, 1995
Summary
Modifying folic acid analogues like ICI 198583 impacts their ability to form polyglutamates, enhancing their anti-cancer activity by improving thymidylate synthase inhibition and cellular retention. Structural changes are key to optimizing these thymidylate synthase inhibitors.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Cancer Biology
Background:
- Quinazoline-based folic acid analogues are thymidylate synthase (TS) inhibitors with anti-cancer potential.
- Their efficacy is linked to intracellular polyglutamation, forming more potent TS inhibitors retained within cells.
- Cell membrane transport and folylpolyglutamate synthetase activity influence this critical polyglutamation process.
Purpose of the Study:
- To investigate how structural modifications of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolate (ICI 198583) affect its polyglutamation.
- To correlate these structural changes with anti-tumour activity and TS inhibition.
Main Methods:
- Intact-cell assays were employed to assess polyglutamation of modified ICI 198583 analogues.
- Structure-activity relationships were analyzed concerning substituents and ring replacements.
- Thymidylate synthase inhibition and cellular growth inhibition were evaluated.
Main Results:
- Modifications like replacing N10 propargyl with smaller aliphatic groups or substituting the benzene ring with heterocycles improved polyglutamation and anti-tumour activity.
- Fluorination, especially adjacent to the bridge region, increased dependence on polyglutamation for activity.
- Certain substituents (CH3, CH2CH3, Br, Cl at C7) significantly reduced or prevented polyglutamation, enhancing TS inhibition and activity under continuous exposure.
- Analogues with 2-CH2OH or NH2 substituents showed reduced polyglutamation and growth inhibition due to poor interaction with the reduced-folate cell membrane carrier.
Conclusions:
- Strategic structural modifications of quinazoline-based folic acid analogues can optimize polyglutamation, leading to enhanced anti-cancer efficacy.
- Understanding the interplay between chemical structure, cellular transport, polyglutamation, and TS inhibition is crucial for developing novel anti-tumour agents.
- Specific modifications can fine-tune the activity profile, making these compounds more potent and suitable for different treatment conditions.